Pharmacokinetics and tissue distribution of the sesquiterpene alpha-humulene in mice.
A quantitative study was undertaken to assess the plasma and tissue levels, tissue distribution and skin (ear) absorption of the sesquiterpene alpha-humulene, the main active constituent isolated from the plant Cordia verbenacea (Boraginaceae ), after oral, intravenous and topical administration in mice. The alpha-humulene levels were quantified by GC-MS analysis. The peak alpha-humulene concentration was achieved 15 min following its oral administration (150 mg/kg). Then, the alpha-humulene plasma concentration gradually decreased and it was almost undetectable at 2 hours after intravenous administration and 12 hours after oral administration. When the oil of C. verbenacea was given orally (1 g/kg), the peak alpha-humulene plasma concentration was observed after 30 min, being detectable only up to 2 h. The oral bioavailability of alpha-humulene was found to be 18 %. The half-lives of alpha-humulene were very short, 16.8 min after oral administration and 1.8 min after intravenous administration. However, the elimination half-lives were longer, 118.2 min and 55 min, for oral and intravenous routes, respectively. We also assessed the amount of alpha-humulene in some selected tissues at 0.5 and at 4 h after oral administration. We found a high amount of the compound in the liver, followed by the kidneys, heart, lungs, spleen and brain, 0.5 h after oral administration. Notably, the yield of alpha-humulene decreased significantly in all analyzed tissues, especially in the liver, 4 h after oral administration. Of note, 30 minutes after topical administration of Acheflan formulations (cream and aerosol) containing 0.5 % of C. verbenacea essential oil, a schedule of treatment that produces marked and similar topical anti-inflammatory activity, the amount of alpha-humulene absorbed in the ear was very similar (about 2 microg/ear). It is concluded that alpha-humulene exhibited a rapid onset and relatively good absorption following oral and topical administration. Taken together, these findings further contribute to an explanation of the topical and systemic anti-inflammatory and antinociceptive properties previously reported for the essential oil and for alpha-humulene obtained from Cordia verbenacea, they also provide support for the clinical studies conducted with the phytomedicine Acheflan.
Chaves
Juliana Siqueira
JS
Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
Leal
Paulo César
PC
Pianowisky
Luis
L
Calixto
João B
JB
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D031213:Cordia / Q000737:chemistry; D005260:Female; D006207:Half-Life; D007668:Kidney / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D008168:Lung / Q000737:chemistry; D008297:Male; D051379:Mice; D015394:Molecular Structure; D000081222:Monocyclic Sesquiterpenes; D009206:Myocardium / Q000737:chemistry; D009822:Oils, Volatile / Q000737:chemistry / Q000493:pharmacokinetics; D010938:Plant Oils / Q000737:chemistry / Q000493:pharmacokinetics; D012717:Sesquiterpenes / Q000737:chemistry / Q000493:pharmacokinetics*; D013154:Spleen / Q000737:chemistry; D014018:Tissue Distribution
D000081222:Monocyclic Sesquiterpenes; D009822:Oils, Volatile; D010938:Plant Oils; D012717:Sesquiterpenes; C042686:humulene